Palladium-catalyzed carbonylative Sonogashira cross-coupling for the synthesis of alkynones with formic acid as the CO source

Article abstract of DOI:10.1007/s00706-018-2331-7

Abstract: A practical and efficient palladium-catalyzed carbonylative Sonogashira cross-coupling reaction for the synthesis of alkynones from aryl iodides, alkynes, and formic acid as the CO source has been described. Under the assistance of PPh₃/I₂, formic acid can be used as the CO source for synthesis of alkynones in moderate–good yields. Furthermore, it is also successfully applied for the modification of natural products, such as vindoline and tabersonin, to obtain the corresponding products.

Full text of DOI:10.1007/s00706-018-2331-7

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2331-7
ORIGINAL PAPER
Palladium‑catalyzed carbonylative Sonogashira cross‑coupling
for the synthesis of alkynones with formic acid as the CO source
Xue Lyu1,2 · Guanglong Sun1,2 · Yang Zhou1,2 · Yingying Wang1,2 · Min Lei1,2 · Wanying Wu1,2 · Dean Guo1,2
Received: 26 July 2018 / Accepted: 6 November 2018
© Springer-Verlag GmbH Austria, part of Springer Nature 2019
Abstract
A practical and efcient palladium-catalyzed carbonylative Sonogashira cross-coupling reaction for the synthesis of alkynones
from aryl iodides, alkynes, and formic acid as the CO source has been described. Under the assistance of PPh3/I2, formic
acid can be used as the CO source for synthesis of alkynones in moderate–good yields. Furthermore, it is also successfully
applied for the modifcation of natural products, such as vindoline and tabersonin, to obtain the corresponding products.
Graphical abstract
Keywords Sonogashira cross-coupling · Aryl iodide · Alkyne · Palladium · Alkynones
Introduction
Alkynones are not only indispensable building blocks for
constructing biologically active molecules [1, 2], natural
products (e.g., anthrapyran metabolites, azaspiracid, and
calystegine B2) [3–5], agrochemicals and pharmaceutical
materials [6], but also serve as versatile synthetic intermedi-
Electronic supplementary material The online version of this
ates in the preparations of heterocycles such as pyrimidines
[2, 7], quinolones [8], furans [9], pyrazoles [10, 11], pyrroles
[12, 13], favones [14], and benzodiazepines [15]. Hence,
the synthesis of alkynones has gained considerable attention
because of their wide application.
article (https://doi.org/10.1007/s00706-018-2331-7) contains
supplementary material, which is available to authorized users.
* Min Lei
mlei@simm.ac.cn
* Wanying Wu
The classical preparative approach of alkynones relies on
cross-coupling reactions of carboxylic acid chlorides with
terminal alkynes or alkynyl organometallic reagents in the
presence of transition metal catalysts [16–20]. However, the
stability and functional group tolerance of the acid chlorides
have hindered extended applications of this methodology.
Since Kobayashi frst reported palladium-catalyzed Sonoga-
shira-type carbonylation in 1981 [21], many enhancements
wanyingwu@simm.ac.cn
1
Shanghai Research Center for Modernization of Traditional
Chinese Medicine, National Engineering Laboratory
for TCM Standardization Technology, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, People’s Republic of China
2
University of Chinese Academy of Sciences, Beijing 100049,
People’s Republic of China
Vol.:(0123456789)
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X. Lyu et al.
and various modifcations of this transformation have been
established [21–34], which can directly convert aryl halides
and terminal alkynes into alkynones in the presence of CO
atmosphere. However, these procedures sufer from the limi-
tations with regard to high pressure and toxicity of CO.
Consequently, great attention has been paid to develop
CO surrogates. In our previous work, we applied CHCl3
as CO precursor in the presence of CsOH·H2O to pro-
duce alkynones in good yields [35]. Additionally, other
CO surrogates, such as methyldiphenylsilane-carboxylic
acid [36, 37], phenyl formate [38], 9-methyl-9H-fuorene-
9-carbonyl chloride [39, 40], formamides [41–44], and
formic acid [45–59], have been explored in this transfor-
mation as well. However, they also have some drawbacks
such as high costs, low yields and harsh reaction condi-
tions. Therefore, it is necessary to search for an efcient,
mild and non-toxic agent as the CO surrogate. Herein, we
developed a palladium–catalyzed carbonylative Sonoga-
shira cross–coupling reaction of aryl iodide, alkynes, and
formic acid as the CO source under the assistance of PPh3/
I2. The results revealed that formic acid could release CO
quickly and efciently in the presence of PPh3/I2 under
mild conditions.
Results and discussion
Initially, we carried out the reaction of iodobenzene (1a),
phenyl acetylene (2a), formic acid, PPh3/I2, Pd(OAc)2 as cat-
alyst, and Et3N as base in toluene. The mixture was stirred
at 60 °C for 8 h, and the desired product 3aa was formed in
68% yield determined by LC–MS. Encouraged by this result,
we carried out a series of optimization experiments with
model reaction and the results are summarized in Table 1.
First, we carried out the model reaction at diferent tem-
peratures, fnding that temperature had a signifcant impact
on the yields of 3aa. As shown in Table 1, 3aa was obtained
without signifcant diference of the yields (65–68%) when
the temperature ranged from 40 to 60 °C (Table 1, entries
3–5). Further increasing the temperature lowers the yields
(Table 1, entries 1–2). The main reason for this phenomenon
was that the main byproduct benzaldehyde 3a was formed.
The results also revealed that 3a could not be formed if
the reaction temperature was not higher than 40 °C. The
desired product 3aa could be obtained in good yields at
40 °C (Table 1, entry 9). Therefore, 40 °C was chosen as
the optimal reaction temperature for all further reactions.
Furthermore, screening of reaction time showed that 4 h was
superior to the others at which 3aa could be obtained in 80%
yield (Table 1, entries 7–11).
Table 1 Optimization of the reaction conditions
Entry
T/ °C
Time/h
Yield/%a
3aa
3a
1
2
3
4
5
6
7
8
80
70
60
50
40
30
40
40
40
40
40
8
8
8
8
8
8
6
5
4
3
2
5
48
68
67
65
33
70
72
80
73
61
55
37
7
3
0
0
0
0
0
9
10
11
0
0
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol, 1.5 equiv), HCOOH (2 mmol, 2 equiv), I2 (1.3 mmol, 1.3 equiv), PPh3 (1.3 mmol, 1.3 equiv),
Pd(OAc)2 (5 mol%), Et3N (6 mmol, 6 equiv), 4 cm3 toluene
aYields were determined by LC–MS
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Palladium-catalyzed carbonylative Sonogashira cross-coupling for the synthesis of alkynones…
Table 2 Substrate scope of aryl
iodides
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol, 1.5 equiv), HCOOH (2 mmol, 2 equiv), I2
(1.3 mmol, 1.3 equiv), PPh3 (1.3 mmol, 1.3 equiv), Pd(OAc)2 (3 mol%), Et3N (5 mmol, 5 equiv),
4 cm3 toluene, 40 °C, 4 h; isolated yields
In addition, the other factors, such as amount of HCOOH,
Under the optimized reaction conditions, the substrate
scope of various aryl iodides and terminal alkynes were
explored. As shown in Table 2, a series of aryl iodides was
applied for this palladium-catalyzed carbonylative Sonoga-
shira cross-coupling reaction. First, to examine the steric
hindrance, ortho, meta, and para substituted substrates were
selected for this cross-coupling reaction. The results showed
that all the substrates reacted smoothly to obtain the desired
products in moderated to good yields (50–85%). The yields
ranged from 68 to 78% when the substrates contained ortho
groups (Me−, NH2−, NO2−, Cl−, and Br−). These results
base, solvents, Pd cat, amount of I2 and PPh3, were also
screened, and the results are provided in the Supplemen-
tary Material. After extensive experimentation, the optimal
condition was established as HCOOH (2 equiv), Pd(OAc)2
(3 mol%), I2 (1.3 equiv), PPh3 (1.3 equiv), Et3N (5 equiv) in
toluene at 40 °C for 4 h. Furthermore, we also tried difer-
ent leaving groups in place of I-, such as Br-, Cl-, TsO-, and
TfO-. However, the desired 3aa was not observed in these
cases (See the Supplementary Material, Table S8).
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X. Lyu et al.
Table 3 Substrate scope of
alkynes
Reaction conditions: 1a (1 mmol), 2 (1.5 mmol, 1.5 equiv), HCOOH (2 mmol, 2 equiv), I2
(1.3 mmol, 1.3 equiv), PPh3 (1.3 mmol, 1.3 equiv), Pd(OAc)2 (3 mol%), Et3N (5 mmol, 5 equiv),
4 cm3 toluene, 40 °C, 4 h; isolated yields
aThis reaction proceeded for 8 h
clearly indicated that the steric hindrance of aryl iodides is
without signifcant efect on this carbonylative Sonogashira
coupling reaction. Moreover, the reaction also showed that
aryl iodides including electron-donating or electron-with-
drawing group could proceed smoothly to form the desired
products. It should be noted that para-nitro and para-cyano
iodobenzenes gave relatively lower yields than other sub-
strates (Table 2, 3ha and 3ia). The main reason for these
results was that aryl iodides with strong electron-withdraw-
ing group were prone to form deiodination products under
these reaction conditions.
Then, we turned our attention to test the generality of
the alkyne coupling partner with various substituted ter-
minal alkynes. As shown in Table 3, all of the substrates
selected could react smoothly with the yields 72–88%.
Moreover, the aliphatic alkyne was successively trans-
formed into the desired product in good yield (3ak, 72%).
To further investigate the application of the Sonogashira
cross-coupling reaction, two alkaloid natural products
(vindoline and tabersonin) were examined (Scheme 1).
The iodo-vindoline (4) and iodo-tabersonin (5) were syn-
thesized according to the reported methods [60, 61]. Then,
1 3

Palladium-catalyzed carbonylative Sonogashira cross-coupling for the synthesis of alkynones…
Scheme 1
the reaction of 4 or 5 with phenylacetylene was carried
out under standard conditions for 4 h. The corresponding
products 15-alkynone-vindoline 6 and 10-alkynone-taber-
sonin 7 were obtained in 60% and 45% yields, respectively.
Based on the experimental results and previous reports, a
plausible reaction mechanism is proposed (Scheme 2) [62].
Initially, I2 and PPh3 formed complex A, which promoted the
release of CO from formic acid. PdII was reduced by PPh3 to
form Pd0 complex B [62]. Through a oxidative addition pro-
cess of aryl iodide to Pd0 to form PdII complex C. Then, CO
was captured by C to form D. After CO insertion, the benz-
oylpalladium halide D converted into arylpalladium alkyne
complex E and released HI simultaneously under the action
of base. Final reductive elimination is furnished to regen-
erate product alkynone and Pd0 complex B that launched
another catalytic cycle.
with various functional groups will make the present method
a useful and important addition to the present methodologies
for the synthesis of alkynones.
Experimental
Reactions were performed in fame-dried glassware using
sealed tube. Liquids and solutions were transferred with
syringes. All solvents and chemical reagents were obtained
from commercial sources and used without further puri-
1
fications. H and 13C NMR spectra were recorded with
tetramethylsilane as an internal reference at 400 MHz and
101 MHz, respectively. Spectra were referenced to the resid-
ual solvent peak of CDCl3 or DMSO-d6 unless otherwise
noted. High-resolution mass spectra (HRMS) were measured
on a Micromass Q-Tof Global mass spectrometer and LCMS
was run on Waters LCMS/SQD+UPLC H-class spectrom-
eter. Flash column chromatography on silica gel (200–300
mesh) was used for the routine purifcation of reaction prod-
ucts. The column output was monitored by analytical thin-
layer chromatography (TLC) on silica gel (100–200 mesh)
precoated on glass plates (15 × 50 mm), and spots were
visualized by ultraviolet light at 254 or 365 nm. Melting
points were recorded on a WRS-1B melting point apparatus.
Conclusion
In conclusion, we have established a convenient and efcient
palladium-catalyzed carbonylative Sonogashira cross-cou-
pling reaction by employing formic acid as the CO source.
The mild reaction conditions, short reaction times, good
yields of the products, ease of work-up, and compatibility
1 3

X. Lyu et al.
Scheme 2
Acknowledgements This work was supported by Special Fund for Stra-
tegic Pilot Technology Chinese Academy of Sciences (XDA12040303).
Commercially available chemicals were obtained from
Acros Organics, Strem Chemicals, Alfa Aesar, Adamas-beta,
J&K, and TCI.
General procedure for the synthesis of compounds
3, 6, and 7
References
1. Savarin CG, Murry JA, Dormer PG (2002) Org Lett 4:2071
2. Karpov AS, Müller TJJ (2003) Org Lett 5:3451
3. Forsyth CJ, Xu J, Nguyen ST, Samdal IA, Briggs LR, Rundberget
T, Sandvik M, Miles CO (2006) J Am Chem Soc 128:15114
4. Marco-Contelles J, de Opazo E (2002) J Org Chem 67:3705
5. Tietze LF, Singidi RR, Gericke KM, Böckemeier H, Laatsch H
(2007) Eur J Org Chem 35:5875
PPh3 (1.3 mmol, 1.3 equiv), I2 (1.3 mmol, 1.3 equiv) and
4 cm3 toluene were added to a 20 cm3 test tube equipped with
a stir bar, which was stirred for 10 min at room temperature.
Then, aryl iodide 1, 4, or 5 (1 mmol), alkyne 2 (1.5 mmol,
1.5 equiv), Pd(OAc)2 (3 mol%), and Et3N (5 mmol, 5 equiv)
were added into the solution. At last, HCOOH (2 mmol, 2
equiv) was added, and the tube was immediately sealed and
stirred at 40 °C for 4 h. After completion of the reaction,
mixture was cooled to room temperature, fltered, and con-
centrated under reduced pressure. The obtained residue was
purifed by fash column chromatography on silica gel to
provide the corresponding products 3, 6, or 7.
6. Chang KT, Choi SH, Kim SH, Yoon YJ, Lee WS (2002) J Chem
Soc Perkin Trans 1:207
7. D’Souza DM, Müller TJJ (2008) Nat Protoc 3:1660
8. Abbiati G, Arcadi A, Marinelli F, Rossi E, Verdecchia M (2009)
Eur J Org Chem 7:1027
9. Kel’in AV, Gevorgyan V (2002) J Org Chem 67:95
10. Grotjahn DB, Van S, Combs D, Lev DA, Schneider C, Rideout M,
Meyer C, Hernandez G, Mejorado L (2002) J Org Chem 67:9200
11. Liu H-L, Jiang H-F, Zhang M, Yao W-J, Zhu Q-H, Tang Z (2008)
Tetrahedron Lett 49:3805
12. Shen J-H, Cheng G-L, Cui X-L (2013) Chem Commun 49:10641
1 3

Palladium-catalyzed carbonylative Sonogashira cross-coupling for the synthesis of alkynones…
13. Kel’in AV, Sromek AW, Gevorgyan V (2001) J Am Chem Soc
123:2074
36. Hu SD, Taaning RH, Lindhardt AT, Skrydstrup T (2011) J Am
Chem Soc 133:18114
14. Sakamoto K, Honda E, Ono N, Uno H (2000) Tetrahedron Lett
41:1819
37. Lescot C, Nielsen DU, Makarov IS, Lindhardt AT, Daasbjerg K,
Skrydstrup T (2014) J Am Chem Soc 136:6142
38. Chavan SP, Bhanage BM (2015) Eur J Org Chem 11:2405
39. Hermange P, Lindhardt AT, Taaning RH, Bjerglund K, Lupp D,
Skrydstrup T (2011) J Am Chem Soc 133:6061
40. Friis SD, Skrydstrup T, Buchwald SL (2014) Org Lett 16:4296
41. Hosoi K, Nozaki K, Hiyama T (2002) Org Lett 4:2849
42. Wan Y, Alterman M, Larhed M, Hallberg A (2002) J Org Chem
67:6232
15. Willy B, Dallos T, Rominger F, Schönhaber J, Müller TJJ (2008)
Eur J Org Chem 28:4796
16. Kalinin VN, Shostakovsky MV, Ponamaryov AB (1990) Tetrahe-
dron Lett 31:4073
17. Delpech B, Calvo D, Lett R (1996) Tetrahedron Lett 37:1019
18. Dodero VI, Koll LC, Faraoni MB, Mitchell TN, Podestá JC (2003)
J Org Chem 68:10087
19. Vong BG, Kim SH, Abraham S, Theodorakis EA (2004) Angew
Chem Int Ed 43:3947
43. Ko S, Lee C, Choi MG, Na Y, Chang S (2003) J Org Chem
68:1607
20. Trost BM, Ball ZT (2004) J Am Chem Soc 126:13942
21. Kobayashi T, Tanaka M (1981) J Chem Soc, Chem Commun
7:333
44. Chen J, Feng J-B, Natte K, Wu X-F (2015) Chem Eur J 21:16370
45. Cacchi S, Fabrizi G, Goggiamani A (2003) Org Lett 5:4269
46. Cacchi S, Fabrizi G, Goggiamani A (2004) J Comb Chem 6:692
47. Korsager S, Taaning RH, Skrydstrup T (2013) J Am Chem Soc
135:2891
22. Ahmed MSM, Mori A (2003) Org Lett 5:3057
23. Liang B, Huang M, You Z, Xiong Z, Lu K, Fathi R, Chen J, Yang
Z (2005) J Org Chem 70:6097
48. Hou J, Xie J-H, Zhou Q-L (2015) Angew Chem Int Ed 54:6302
49. Qi X, Jiang L-B, Li C-L, Li R, Wu X-F (2015) Chem Asian J
10:1870
24. Sans V, Trzeciak AM, Luis S, Ziólkowski JJ (2006) Catal Lett
109:37
25. Liu J, Peng X, Sun W, Zhao Y, Xia C (2008) Org Lett 10:3933
26. Fusano A, Fukuyama T, Nishitani S, Inouye T, Ryu I (2010) Org
Lett 12:2410
50. Qi X, Jiang L-B, Li H-P, Wu X-F (2015) Chem Eur J 21:17650
51. Qi X, Li C-L, Jiang L-B, Zhang W-Q, Wu X-F (2016) Catal Sci
Technol 6:3099
27. Wu X-F, Neumann H, Beller M (2010) Chem Eur J 16:12104
28. Wu X-F, Sundararaju B, Neumann H, Dixneuf PH, Beller M
(2011) Chem Eur J 17:106
52. Qi X, Li C-L, Wu X-F (2016) Chem Eur J 22:5835
53. Jiang L-B, Li R, Li H-P, Qi X, Wu X-F (2016) ChemCatChem
8:1788
29. Wu X-F, Sundararaju B, Anbarasan P, Neumann H, Dixneuf PH,
Beller M (2011) Chem Eur J 17:8014
54. Qi X, Li H-P, Wu X-F (2016) Chem Asian J 11:2453
55. Qi X, Li R, Wu X-F (2016) RSC Adv 6:62810
56. Jiang L-B, Qi X, Wu X-F (2016) Tetrahedron Lett 57:3368
57. Ren W, Chang W, Dai J, Shi Y, Li J, Shi Y (2016) J Am Chem Soc
138:14864
30. Wu X-F, Neumann H, Beller M (2011) Org Biomol Chem 9:8003
31. Wu X-F, Neumann H, Beller M (2011) Angew Chem Int Ed
50:11142
32. Kim W, Park K, Park A, Choe J, Lee S (2013) Org Lett 15:1654
33. Natte K, Chen J, Neumann H, Beller M, Wu X-F (2014) Org
Biomol Chem 12:5590
58. Seo Y-S, Kim D-S, Jun C-H (2016) Chem Asian J 11:3508
59. Peng J-B, Qi X, Wu X-F (2017) Synlett 28:175
60. Johnson PD, Sohn JH, Rawal VH (2006) J Org Chem 71:7899
61. Lewin G, Rolland Y, Poisson J (1980) Heterocycles 14:1915
62. Amatore C, Jutand A (2000) Acc Chem Res 33:314
34. Li W, Wu X-F (2015) Org Biomol Chem 13:5090
35. Sun G, Lei M, Hu L (2016) RSC Adv 6:28442
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